ANTIPLATELET THERAPHY

ANTIPLATELET THERAPHY

            These are the drugs which interfere with platelet function and may be useful in pophylaxis of thromboembolic disorders. Platelet sticks to the damaged vessel wall, then they stick to each other (aggregate) and release ADP, TXA2 with promote further aggregation. Thus platelet plug is formed. In the vein, due to sluggish blood flow, a fibrinous tail is formed which traps RBC. “The Red Tail”. In arteries, platelet mass is the main constituent of the thrombus, antiplatelet drugs are, therefore more useful in arterial thrombosis while, anticogulants are more effective in venous thrombosis.

            PgI2, synthesis in intima of blood vessels is the strong inhibitors of platelet aggregation. The balance between TXA2 release from platelets and PGI2 released from vessel wall appears to control intravascular thrombus formation. Platelets also play a role in atherogenesis. Drug interfering with platelet functions are;

1. Aspirin
2. Sulfinpyrazole
3. Dipyridanole
4. Ticlopidene

            People with diabetes have a two to fourfold increase in the risk of dying from the complications of cardiovascular disease. Both men and women are at increased risk. Atherosclerosis and vascular thrombosis are major contributors, and it is generally accepted that platelets are contributory.  Platelets from men and women with diabetes are often hypersensitive in vitro to platelet aggregating agents. A major mechanism is increased production of thromboxane, a potent vasoconstrictor and platelet aggregant. Investigators have found evidence in vivo of excess thromboxane release in type 2 diabetic patients with cardiovascular disease. Aspirin blocks thromboxane synthesis by acetylating platelet cyclo-oxygenase and has been used as a primary and secondary strategy to prevent cardiovascular events in non-diabetic and diabetic individuals.

            Antiplatelet therapy in men and women after myocardial infarction, stroke or transient ischemic attack, or stroke or transient ischemic attack, or positive cardiovascular history (vascular surgery, angioplasty, angina etc) has been reported by the Anti-Platelet Trialists (APT). Reductions in vascular events were about one qurter in each of these categories, and diabetic subjects had risk reductions that were comparable to non-diabetic individuals. There was a trend toward increased risk reductions with doses of aspirin of 325 mg/day or less.

            Aspirin significantly reduced cardiovascular events by 15% and myocardial infarction by 36%. The relative effects of aspirin were similar in nondiabetic and diabetic subjects. Fatal bleeding episodes including intracerebral bleeding episodes were more common in the aspirin group.

            Primary prevention trial in which a low dose aspirin regimen (325mg every other day). There was a 44% risk reduction in the treated group.

            A major risk of aspirin therapy is gastric mucosal injury and gastrointestinal hemorrhage. Minor bleeding episodes (epistaxis, bruising etc) may occur at low doses, probably from the effect of aspirin to inhibit the platelet release reaction. Contraindications to aspirin therapy include allergy, bleeding tendency, anticoagulant therapy, recent gastrointestinal bleeding, and clinically active hepatic disease.

            Aspirin therapy conveyed no increase in benefit or in risk regarding progression of diabetic retinopathy and maculopathy. Regular use of nonsteroidal anti-inflammatory drugs may increase the risk for chronic renal disease and may impair blood pressure control in hypertensive patients. However, a low dose of aspirin is a very weak inhibitor of renal prostaglandin synthesis and has no clinically significant effect on renal function or on blood pressure control.

            The platelet release reaction is exquisitely sensitive to inhibition by aspirin. In this regard, it has been shown that a dose as low as 75mg of enteric coated aspirin is just as effective as higher doses of either plain or enteric coated aspirin in inhibiting thromboxane synthesis. The results achieved with various doses of aspirin, alone or in combination with other antiplatelet agents, including dipyridamole and sulfinpyrazone. No evidence was found that combinations of aspirin with other antiplatelet drugs were any more effective than aspirin alone. Platients with or without diastolic hypertension, those over or under age 65 years, and in diabetic and nondiabetic subjects.  Absolute benefit was greater among those at high risk (over age 65 years, diastoclic hypertension, diabetes) the use of one to six aspirins a week is associated with a reduced risk for myocardial infarction in women. Diabetes appears to place women at high risk for myocardial infarction. In diabetic subjects, agents such as clopidogrel may be considered as a substitute in the case of aspirin allergy. Clopidogrel (75mg) was slightly more effective than aspirin (325mg) in reducing the combined risk of stroke, myocardial infarction, or vascular death in diabetic and non-diabetic subjects.

            Aspirin - It acetylates and inhibits the enzyme cycloxygenase and Tx synthetase inactivating them irreversibly. TXA2 formation is suppressed at very low doses and till fresh platelets are formed. Thus, aspirin induced prolongation of BT lasts 5-7 days. Effects of daily doses cumulative and it have doses as low as 40mg/day are effective and maximal inhibition of platelet function occurs at ³ 160mg aspirin/day. Aspirin inhibits PgI2 synthesis  in vessel wall low doses (40-150mg/day or 300mg twice weekly) TXA2 formation by platelets is selectively suppressed whereas higher doses (>900mg/day) may decrease both TXA2 and PgI2 production.

            Aspirin inhibitors the release of ADP from platelets and their sticking to each other. However, it has no effect on platelet survival time and their adhesion to damaged vessel wall.

Dipyridamole – It is a vasodilatar which was introduced for angina pectoris, it inhibits phosphodiestras and blocks uptake of adenosine to increase platelet CAMP which potentiate PgI2 and interferes with aggregation. Levels of TxA2/PgI2 are not altered but platelet survival time reduced by disease is normalized. It improves the response to warfarin, along with which it is used to decrease the incidence of thromboembolism in patient with prosthetic heart valve. It has also been used to enhance antiplatelet action of aspirin.

Ticlopidine – It is a newer drug which directly interacts with platelet membrane, alters the fibrinogen receptor in such a way that fibrinogen is not able to bind to the activated platelets. Thus platelet aggregation and clot retraction are inhibited. It has no effect on platelet CAMP or TXA2, but prolongs bleeding time and increased platelet survival in extracorporeal circulation. Beneficial effect in stroke prevention TIAs, intermittent claudication, unstable angina, CABG and secondary prophylaxis of MI. side effect; Diarrhea, vomiting, abdominal pain, headache, tinnitus, skin rash, bleeding, neutropenia and jaundice.

Uses of Antiplatelet Drugs

1. Coronary Artery Disease MI

Low dose aspirin started immediately after MI has been found to reduce mortality and prevention re-infarction. It also improves survival when used along with thrombolytic therapy with or without heparin. It is now routinely used to prevent reocclusion after thrombolytic therapy. It is also given along with heparin to cover PTCA and then continued indefinitely. Unstable angina aspirin reduce the risk of MI and sudden death in patient with unstable angina. For maximum benefit aspirin 100-150mg/day is given along with heparin followed by warfarin. Primary and secondary of MI – In post MI, it has been recommended that aspirin 40-325mg/day (usually 75-150mg/day) be given to all individual with evidence of CAD and in those with risk factor for the same, but routine use in the whole population is not warranted. Aspirin reduced the incidence of fatal as well as non fatal MI, but increased the risk of cerebral hemorrhage; overall mortality was only marginally reduced.

2. Cerebrovascular Disease

Antiplatelet drugs do not alter the course of stroke due to cerebral thrombosis. However, aspirin has reduced the incidence of TIAS, of stroke in patient with TIAS as well as persistant AF and those in with history of stroke in the past. It is recommended in all such individuals, ticlopidine also reduces TIA and stroke.

3. CABG Implants

The patency of the implanted by pass vessel is improved and incidence of reocclusion is reduced by aspirin or ticlopidine. Aspirin started just after the operation is considered the best choice.

4. Prosthetic Heart Valves and AV Shunts

Antiplatelet drugs used with warfarin reduce the formation of microthrombi on artificial heart valves and incidence of embolism. Aspirin is clearly effective but increases risk of bleeding due to warfarin. Diplyridamole does not increased bleeding risk, but its efficacy has been doubted. Antiplatelet drugs also prolong the patency of chronic AV shunts implanted for hemodialysis and of vascular grafts.

5. Venous Thromboembolism

Anticogulatnts are routinely used. Antiplatelet drugs also to have a proplhylactic effects.

6. PVD Peripheral Vascular Disease

Aspirin and ticlopidine may produce some improvement in intermittent claudication and reduce the incidence of thromboembolism.

Note:

1. Use aspirin therapy as a secondary prevention strategy in diabetic men and women who have evidence of large vessel disease. This includes diabetic men and women with a history of myocardial infarction, vascular bypass procedure, stroke or transient ischemic attack, peripheral vascular disease, claudication and or angina.
2. In addition to treating the primary cardiovascular risk factor(s) identified, consider aspirin therapy as a primary prevention strategy in high risk men and women with type 1 or type 2 diabetes. This includes diabetic subjects with the following.
• A family history of coronary heart disease
• Cigarette smoking
• Hypertension
• Obesity (>120% desirable weight), BMI>27.3kg/m² in women, >27.8kg/m² in men.
• Albuminuria (micro or macro)
• Lipids: Cholesterol >200mgdl

LDL cholesterol ³ 100mg/dl

HDL cholesterol <45mg/dl in men and <55mg/dl in women

Triglycerides>200mg/dl

• Age >30 years

Use of aspirin has not been studied in diabetic individuals under the age of 30 years.

3. Use enteric coated aspirin in doses of 81-325 mg/day.
4. People with aspirin allergy, bleeding tendency, anticoagulant therapy, recent gastrointestinal bleeding and clinically active hepatic disease are not candidates for aspirin therapy.
5. Aspirin therapy should not be recommended for patients under the age of 21 years because of the increased risk of Reye’s syndrome associated with aspirin use in this population.

REFERENCE:

            Essential of Medical Pharmacology, Tripati and Clinical Practice Recommendations, ADA